CITRATE DIALYSIS FLUID

WHAT IS CITRATE? Citrate is a natural metabolite, which is a source of cellular energy, providing buffering capacity to the patient. Citrate is an intermediate in the citric acid cycle and is widely used in the food and drug industry because of its buffering, anticoagulant and antioxidant capacities.

As a chelator, citrate is able to bind calcium and metals that catalyse the production of Reactive Oxygen Species.1

Under physiologic circumstances, citrate is metabolized in the liver, skeletal muscle and renal cortex.2

Citrate clearance is not impaired in patients with chronic renal failure.3

WHY CITRATE IN DIALYSIS? An acid is required in bicarbonate dialysis to avoid insoluble calcium and magnesium precipitation. Acetic acid is commonly used at a concentration up to one hundred times higher than normal plasma acetate levels.4 Body gain of acetate is particularly high in convective treatments.5 This results in a substantial increase in plasma acetate which may promote hemodynamic instability, inflammation and acidosis.4

Citric acid has been proposed as an alternative dialysis buffer due to its anticoagulant, anti-inflammatory and anti-oxidant properties.6

WHAT IS THE INTENDED USE OF SOFTPAC CITRATE AND SELECTBAG CITRATE IN HEMODIALYSIS?HD concentrate Citrate product is intended to be used as a citrate based acid concentrate in bicarbonate dialysis for on-line preparation of hemodialysis, hemodiafiltration and hemofiltration fluids on compatible dialysis machines.*

CITRATE IN DIALYSIS

* Baxter SoftPac Citrate and SelectBag Citrate Instruction for Use.

The Baxter SoftPac Citrate andSelectBag Citrate concentrateallows for acetate-free dialysis fluids which may help to promote patient well-being with all the beneficial properties of Citrate.1

ARE YOU AWARE OF THE BIOCOMPATIBLE PROPERTIES OF CITRATE?4,7

In vitro data show that:• low concentration of citrate can reduce complement and granulocyte activation

in human whole blood.7 • the dispensation of citrate per se reduces endothelial death and inflammation

in a hyperglycemic environment.1

• at concentration commonly used in clinical practice, acetate dialysate increases oxidative stress and may act as an adjunct to the other proinflammatory stimuli to which HD patients are exposed. Citrate dialysate does not produce such a cell activation.8

• citrate dialysis reduces endothelial cell dysfunction and vascular smooth muscular cell osteoblastic differentiation.6

• citrate dialysate favorably affects calcification propensity.9

Ex-Vivo data show that:Citrate-acidified bicarbonate dialysis protects against calcium accumulation in rat aortic walls cultured ex vivo.10

In clinical trialsBaxter citrate concentrate fluid has been shown:• to reduce the intra-dialytic rise in pentraxin-3 (PTX3) compared to control

in a short-term randomized controlled cross-over study. PTX3 is an inflammatory marker known to be induced by HD treatments.4

• to lower pre-dialysis levels of the inflammatory marker C-reactive protein (CRP) in a controlled cross-over study in patients in on-line haemodiafiltration.11

• to significantly reduce chronic inflammation parameters such as CRP, fibrinogen, IL6, and adipokine chemerin when switching from acetate to citrate in a cross-over study, patients being treated in sequence with acetate, citrate and again acetate buffered dialysis solutions.6

In this randomized cross-over study the duration was 9 months; in the first 3 months patients were treated with a standard dialysis solution containing 3 mmol/l acetate, the following 3 months an acetate-free solution containing 1 mmol/L citrate (Select Bag Citrate) and the last 3 months again the acetate solution were used.

Patients’ clinical data at the different study time points, (D) pre-dialysis values of plasma C-Reactive Protein (CRP), (E) pre-dialysis plasma fibrinogen, (F) pre-dialysis serum IL6. T0: study start; T1: end of 1st acetate period (3 months from study start); T2 end of citrate (6 months); T3 end of 2nd acetate period (9 months).*p < 0.05 when data were compared with T1; #p < 0.05 when data were compared with T2.Adapted from Dellepiane6 N=45

CITRATE IN DIALYSIS

Chronic HD patients suffer from high cardiovascular morbidity and mortality mainly due to a chronic systemic inflammation coupled with an aberrant metabolic state6

In vitro studies show that citrate is a promising substitute for acetate for a more biocompatible dialysis, most likely

resulting in less adverse effects for the patients7

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Citrate is rapidly metabolized in the body into bicarbonate in a 1:3 molar ratio.17

Patients with reduced kidney function are in positive acid balance. During each HD session, a large surge of HCO3

- enters the circulation and typically overcorrects predialysis acidosis to alkalosis and alkalemia. The acid-base alterations may have an impact on cardiovascular system, central nervous system, pulmonary function, tissue oxygenation and metabolism, inflammation and defense against infection.18

Since 2000, KDOQI guidelines recommend maintaining predialysis serum bicarbonate at ≥ 22 mmol/L.19

As documented by the DOPPS, both high (>27 mEq/L) and low (≤17 mEq/L) serum bicarbonate levels are associated with increased risk for mortality and hospitalization.21 A more recent publication showed an increase in mortality with low serum bicarbonate, but did not show the same increase in mortality with higher serum bicarbonate levels.20

IMPROVED CONTROL OF ACID-BASE BALANCE

Citrate dialysate helps to control acid base balance by correcting acidosis between sessions and avoiding/reducing post dialysis alkalosis. Acute alkalaemia induced by the addition of (missing) bicarbonate during dialysis is an issue which has considerable clinical significance. It has been related to important adverse effects, such as hemodynamic instability, cardiac arrhythmia, paraesthesia/cramps, reduced cerebral blood flow, respiratory distress, headache, and a procalcifying effect.22

ACIDOSIS & ALKALOSIS PREVENTIONCORRECTED BETWEEN-TREATMENT ACIDOSIS AND REDUCED POST-TREATMENT ALKALOSIS

In a prospective, multicenter, randomized and crossed study, of 32 weeks duration, in patients in three-week HD, 16 weeks with ADF (acetate dialysis fluid) and 16 weeks with CDF (citrate dialysis fluid) SelectBag Citrate. Dialysis with citrate achieves a better control of post-dialysis acid-base balance by decreasing/avoiding post-dialysis alkalemia compared to acetate.12

PRE-HEMODIALYSIS POST-HEMODIALYSIS SIGNIFICANCE

ADF CDF ADF CDF ADF-CDF ADF-CDF

Bicarbonate, mmol/l 23.0 (1.87) 22.8 (2.20) 28.5 (3.0) 26.9 (1.5) 0.668 0.032

A recent randomized controlled study has shown that compared to acetate dialysates, citrate containing fluids may offer a greater hemodynamic stability with significantly fewer episodes of arterial hypotension.12

This is aligned with the results of previous studies: • reduction in the frequency of hypotensive episodes, especially in the most

symptomatic and severe episodes of hypotension.13

• the use of citrate rather than acetate as a dialysate decreases peripheral resistances and slightly reduces systolic and diastolic blood pressure. Nonetheless, both the analysis of maximum fluctuations in peripheral resistances during dialysis and data describing subjective tolerance suggest a trend towards improved haemodynamic stability for patients on the citrate schedule.14

IMPROVED HEMODYNAMIC STABILITY

WHY IS IT IMPORTANT TO REDUCE INTRADIALYTIC HYPOTENSION? In addition to a reduced sense of well-being caused by the symptoms of intradialytic hypotension (IDH), patients who experience IDH have been shown to be at higher risk of mortality.15,16

In a prospective, multicenter, randomized and crossed study of 32 weeks duration, with 56 patients randomly assigned to receive 16 consecutive weeks of citrate concentrate followed or preceded by 16 weeks of acetate fluid, there were fewer episodes of hypotension during the sessions at the baseline visit with the citrate concentrate (1 versus 3, p=0.04). The 46 patients who completed the study performed 4416 HD sessions, 2208 with acetate and 2208 with citrate. Hypotension occurred in 14.1% with acetate versus 10.8% with citrate (p<0.01).12

Adapted from de Sequera12 N=56

DECREASED THROMBOGENICITYBy chelating ionized calcium in plasma, citrate containing dialysate concentrates have anticogulant properties in a concentration-dependent manner:• Citrate fluid induces a significant intradialytic increase in aPTT (activated partial

thromboplastin time).4

• Citrate has local anticoagulant effect inside the dialyzer, allowing reduced heparin dosing while maintaining extracorporeal patency23 and optimizing dialyzer clearances .4,6,11

SoftPac Citrate and SelectBag Citrate products are not intended to obviate the need for anticoagulation in all patients.24

ALTERNATIVE MODE OF LOW SYSTEMIC ANTICOAGULATIONThe combination of citrate dialysate with the heparin–grafted membrane Evodial has been shown to be a valid alternative to regional citrate anticoagulation.23,25,26

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Increased Activated Partial Thromboplastin Time (APTT) post dialysis when using SelectBag Citrate dialysis fluid.1 Solid bars represent pre-dialysis values and shadowed bars post-dialysis values. Data are shown as means ±SEM, p*=0.003. Adapted from Grundstrom.4 N=24

In this randomized cross-over study the duration was 9 months; in the first 3 months patients were treated with a standard dialysis solution containing 3 mmol/l acetate, the following 3 months an acetate-free solution containing 1 mmol/L citrate (Select Bag Citrate) and the last 3 months again the acetate solution were used.

Patients’ clinical data at the different study time points, (A) Pre-dialysis blood urea nitrogen levels, (B) pre-dialysis serum creatinine values, (C) dialysis efficacy estimated with the eKt/V Daugirdas formula. Period (3 months from study start); T2 end of citrate (6 months); T3 end of 2nd acetate period (9 months).*p < 0.05 when data were compared with T1; #p < 0.05 when data were compared with T2.Adapted from Dellepiane6 N=45

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In an open-labeled cross-over trial (6+6) weeks with 8 treatments wash-out in between. Patients were randomly assigned to start with either citrate dialysis fluid rate or control acetate fluid.

Citrate binds ionized calcium and causes a change in the total calcium mass transfer compared to dialysis fluids without citrate, unless compensated for. A kinetic model developed by Baxter Research shows that with one mmol/l of citrate in the dialysis fluid an additional 0.15 mmol/l of calcium is required to achieve a mass balance within the dialyzer that is equivalent to dialysis fluid without any citrate.27 Clinical data support these theoretical results.4,28,29

Baxter citrate concentrates offer augmented calcium concentration, making it easy to maintain the proper calcium mass balance.

THE EFFECT OF CITRATE ON CALCIUM BALANCE

Some patients may not benefit from the use of citrate dialysate and need to be closely monitored: patients with hypocalcemia, hypomagnesemia and uncontrolled secondary hyperparathyroidism.12

CITRATE DIALYSIS

Citrate is a well-known antioxidant and anticoagulant buffer that is a well-tolerated and biocompatible alternative to regular acetate.

Citrate-containing acetate free dialysis is suitable for every patient.

CITRATE CLINICAL ADVANTAGES:• Improved hemodynamic stability• Improved control of acid-base balance• Decreased thrombogenicity

Calcium mass balance is easily maintained during treatment

Suitable for every patient

Baxter, Gambro, Evodial, SelectBag and SoftPac are trademarks of Baxter International Inc. or its subsidiaries. GLBL/MG200/17-0001(5) – January 2020

renalcare.baxter.com Baxter Healthcare Corporation

One Baxter ParkwayDeerfield, IL 60015

USA1-800-422-9837

1. Bryland A, Wieslander A, Carlsson O et al. Citrate treatment reduces endothelial death and inflammation under hyperglycaemic conditions. Diab Vasc Dis Res 2012; 9(1): 42-51.

2. Zheng Y, Xu Z et al. Citrate Pharmacokinetics in Critically Ill Patients with Acute Kidney Injury. PLoS ONE 2013; 8(6): e65992.3. Bauer E., Derfler K. Et al. Citrate Kinetics in Patients Receiving Long-Term Hemodialysis Therapy. Am J Kidney Dis 2005; 46:903-907.4. Grundstrom G, Christensson A, Alquist M et al. Replacement of acetate with citrate in dialysis fluid: a randomized clinical trial of short term

safety and fluid biocompatibility. BMC Nephrol 2013, 14:216.5. Pizzarelli F, Cerrai T et al. On-line haemodiafiltration with and without acetate. Nephrol Dial Transplant 2006; 21: 1648-1651.6. Dellepiane S, Medica D., Guarena C et al. Citrate anion improves chronic dialysis efficacy, reduces systemic in-flammation and prevents

Chemerin-mediated microvascular injury. Sci Rep 2019; 9: 10622.7. Huang S, Sandholm K, Jonsson N et al. Low concentrations of citrate reduce complement and granulocyte activation in vitro in human blood.

Clin Kidney J 2015; 8: 31-37.8. Perez-Garcia R, Rafael Ramirez Chamond RR, De Sequera Ortiza P et al. Citrate dialysate does not induce oxidative stress or inflammation

in vitro as compared to acetate dialysate. Nefrologia 2017; 37(6): 630-637.9. Lorenz G, Mayer C et al. Acetate-free, Citrate-acidified bicarbonate dialysis improves serum calcification propensity—a preliminary study.

Nephrol Dial Transplant 2018; 33(11): 2043-2051.10. Villa-Bellosta R. et al. Impact of acetate- or citrate-acidified bicarbonate dialysate on ex vivo aorta wall calcification. Sci Rep 2019; 9: 11374.11. Molina Nunez M, de Alarcon R et al. Citrate versus Acetate-Based Dialysate in On-Line Haemodiafiltration. A Pro-spective Cross-Over Study.

Blood Purif 2015; 39:181–187.12. de Sequera P, Garciaa R P, Molina M et al. Prospective randomized multicenter study to demonstrate the benefits of haemodialysis without

acetate (with citrate):ABC-treat Study. Acute effect of citrate. Nefrologia 2019; 39(4): 424-433.13. Daimon S, Dan K, Kawano M. Comparison of acetate-free citrate hemodialysis and bicarbonate hemodialysis re-garding the effect

of intra-dialysis hypotension and post-dialysis malaise. Ther Apher Dial 2011; 15(5): 460-5.14. Gabutti L, Lucchini B et al. Citrate- vs. acetate-based dialysate in bicarbonate haemodialysis: consequences on haemodynamics,

coagulation, acid-base status, and electrolytes. BMC Nephrol 2009, 10: 7.15. Stefansson B, Brunelli S et al. Intradialytic Hypotension and Risk of Cardiovascular Disease Clin J Am Soc Nephrol 2014; 9: 2124–2132.16. Chou J, Streja E, Intradialytic hypotension, blood pressure changes and mortality risk in incident hemodialysis patients.

Nephrol Dial Transplant 2018; 33: 149–159.17. Monchi M. Citrate pathophysiology and metabolism Transfus Apher Sci 2017; 56(1): 28–30.18. Qian Q. Acid-base alterations in ESRD and effects of hemodialysis. Semin Dial. 2018; 31: 226–235.19. K/DOQI Clinical practice guidelines for nutrition in chronic renal failure. Am J Kidney Dis 2000; 35[Suppl 2]: S1–S140.20. Tentori F, Karaboyas A et al. Association of Dialysate Bicarbonate Concentration with Mortality in the Dialysis Outcomes and Practice Patterns

Study (DOPPS) Am J Kidney Dis. 2013; 62(4).21. Bommer J, Francesco Locatelli F et al. Association of Predialysis Serum Bicarbonate LevelsWith Risk of Mortality and Hospitalization in the

Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis 2004; 44(4): 661-671.22. De Sequera Ortiz P, Albalate Ramon M et al. Acute effect of citrate bath on postdialysis alkalaemia. Nefrologia 2015; 35:164-71.23. Meijers B., Christoph Metalidis C. et al. A noninferiority trial comparing a heparin-grafted membrane plus citrate-containing dialysate versus

regional citrate anticoagulation: results of the CiTED study. Nephrol Dial Transplant 2017; 32: 707–714.24. Dolley-Hitze T, Is Anticoagulation Discontinuation Achievable with Citrate Dialysate during HDF Sessions? Int J Nephrol. 2016; 7: 1-8.25. Karlien F et al. Avoidance of systemic anticoagulation during intermittent haemodialysis with heparin-grafted pol-yacrilonitrile membrane

and citrate-enriched dialysate: a retrospective cohort study. BMC Nephrol 2014; 15:104.26. Skagerlind M, Stegmayr B. An evaluation of four modes of low-dose anticoagulation during intermit-tent haemodialysis.

Eur J Clin Pharmacol 2018; 74:267–274.27. Nilsson A, Sternby J, Grundstrom G, Alquist M. Citrate dialysis fluid and calcium mass balance. Nephrol Dial Transplant 2013;28 (suppl1): i207.28. Steckiph D, Bertucci A, Petrarulo M et al. Calcium mass balances in on-line HDF using citrate-containing acetate-free and regular dialysis

concentrates. Nephrol Dial Transplant 2013;28 (suppl1).29. Teatini U. et al, Calcium mass balance of an acetate free citrate containing dialysis fluids: Ad interim analysis of citrus study.

Nephrol Dial Transplant. 2017; 32 (Supplement 3): iii78-iii79.

REFERENCES